Dopamine D4 ligands for the treatment of novelty-seeking disorders

ABSTRACT

The present invention provides a method of treating or preventing a novelty-seeking disorder such as pathological gambling, attention deficit disorder with hyperactivity disorder, substance addiction, drug addiction, alcohol addiction and sex addiction. using a compound which is a dopamine D4 receptor ligand, or a pharmaceutically acceptable salt thereof.

[0001] The present invention relates to a method of treating orpreventing a novelty-seeking disorder selected from pathologicalgambling, attention deficit disorder with hyperactivity disorder,substance addiction, such as drug addiction and alcohol addiction, andsex addiction, using a dopamine D4 ligand. It also relates to a methodof treating or preventing such disorders in mammals by administering apyrido[1,2a]pyrazine derivative, benzimidazole derivative, bicycliccompound, spirocyclic benzo furan derivative, indole derivative or arelated compound that is a dopamine D4 receptor ligand.

[0002] It has been determined that dopamine D4 receptors are related tovarious behavioral and personality disorders including novelty seekingdisorders (See, e.g., Tarazi et al., Mol. Psychiatry, 4, 529-538(1999).The trait of novelty seeking was found to be related to dopaminergicactivity in alcoholic men (Wiesbeck et al., Psychoneuroendocrinology,20, 7(1999)). A large Finnish study provides support for an associationbetween the D4 receptor gene (DRD4) and the behavioral trait of noveltyseeking (Ekelund et al., Am. J. Psychiatry, 156, 1453-5 (1999)). Recentevidence has accumulated which supports a clinical linkage betweenattention deficit disorder with hyperactivity disorder, which has beenassociated with the novelty seeking trait, and dopamine receptorexpression (see, e.g., Tarazi et al., supra; Anderson et al.,Neuroscience & Biobehavioral Rev., 24, 137-41 (2000)) and dopaminetransporter gene expression (see, e.g., Dougherty et al., The Lancet,354, 2132-2133 (1999)). Further evidence has been found for anassociation between the D4 gene and a susceptibility to pathologicalgambling (Comings, CNS Spectr., 3, 20-37 (1998)) and a susceptibility toopioid addiction and substance abuse (Kotler et al., Mol. Psychiatry, 2,251-254 (1997)).

[0003] The following references refer, collectively, topyrido[1,2a]pyrazine derivatives, benzimidazole derivatives, bicycliccompounds, spirocyclic benzofuran derivatives, indole derivatives orrelated compounds that exhibit activity as dopamine D4 receptor ligands:U.S. Pat. No. 5,852,031, issued on Dec. 22, 1998; U.S. Pat. No.5,883,094, issued on Mar. 16, 1999; U.S. Pat. No. 5,889,010, issued onMar. 30, 1999; PCT International Application PCT/IB97/00978, publishedas WO98/08835 on Mar. 5, 1998; U.S. patent application Ser. No.5,877,317 issued on Mar. 2, 1999; U.S. patent application Ser. No.5,021,420, issued on Jun. 4, 1991; U.S. patent application Ser. No.5,633,376, issued on May 27, 1997; U.S. patent application, Ser. No.5,432,177, issued on Nov. 9, 1994; U.S. patent application Ser. No.5,622,950, issued on Apr. 22, 1997, PCT International Application No.PCT/EP93/01438, published as WO94/00458 on Jan. 6, 1994; PCTInternational Application No. PCT/IB98/01198, published as WO99/09025 onFeb. 25, 1999; U.S. patent application Ser. No. 5,998,414, issued onDec. 7, 1999; U.S. patent application Ser. No. 5,968,478, issued on Oct.19, 1999; U.s. patent application Ser. No. 6,040,448, issued on Mar. 21,2000; U.S. patent application Ser. No. 6,051,605, issued on Apr. 18,2000; U.S. patent application Ser. No. 5,945,421, issued on Aug. 31,1999; and U.S. patent application Ser. No. 5,798,350, issued on Aug. 25,1998. All of the foregoing PCT International Applications designate theUnited States. The foregoing patents and patent applications areincorporated by reference in their entirety.

SUMMARY OF THE INVENTION

[0004] This invention relates to a method of treating or preventing anovelty-seeking disorder selected from pathological gambling, attentiondeficit disorder with hyperactivity disorder (ADHD), substance addiction(e.g., drug addiction and alcohol addiction) and sex addiction in asubject, including a human, comprising administering to the subject aneffective amount of:

[0005] (a) a compound of formula I:

[0006]  wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl,indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl,benzothienyl, oxazolyl, or benzoxazolyl;

[0007] Ar¹ is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzisoxazolyl, or benzisothiazolyl; A is O, S, SO, SO₂, C═O, CHOH, or—(CR³R⁴)—; n is 0, 1 or 2; each of Ar and Ar¹ may be independently andoptionally substituted with one to four substituents independentlyselected from the group consisting of fluoro, chloro, bromo, iodo,cyano, nitro, thiocyano, —SR, —SOR, —SO₂R, —NHSO₂R, —(C1-C6)alkoxy,—NR¹R², —NRCOR¹, —CONR¹R², Ph, —COR, COOR, —(C₁-C₆)alkyl, —(C₁-C₆)alkylsubstituted with one to six halogens, —(C₃-C₆)cycloalkyl, andtrifluoromethoxy;

[0008] each and every R, R¹, and R² is independently selected from thegroup consisting of hydrogen, —(C₁-C₆)alkyl, —(C₁-C₆)alkyl substitutedwith one to thirteen halogens selected from fluorine, chlorine, bromineand iodine, phenyl, benzyl, —(C₂-C₆)alkenyl, —(C₃-C₆)cycloalkyl, and—(C₁-C₆)alkoxy;

[0009] each and every R³ and R⁴ is independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, or i-propyl;diastereomeric and optical isomers thereof; and pharmaceuticallyacceptable salts thereof;

[0010] (b) a compound of formula II: II:

[0011]  wherein X¹, X² and X³ are independently selected from carbon andnitrogen;

[0012] R⁰, R¹ and R² are independently selected from hydrogen, halo(e.g., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionallysubstituted with from one to three fluorine atoms and (C₁-C₆)alkoxyoptionally substituted with from one to three fluorine atoms;

[0013] R³ is hydrogen, (C₁-C₆)alkyl or benzyl, wherein the phenyl moietyof said benzyl group may optionally be substituted with from one or moresubstituents, preferably with from zero to three substituents,independently selected from halo (e.g., chloro, fluoro, bromo or iodo),cyano, (C₁-C₆)alkyl optionally substituted with from one to threefluorine atoms, (C₁-C₆)alkoxy optionally substituted with from one tothree fluorine atoms, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylamino, amino,di—(C₁-C₆)alkylamino and (C₁-C₆)carboxamido;

[0014] R⁴, R⁵ and R⁶ are independently selected from hydrogen, halo(e.g., chloro, fluoro, bromo or iodo), cyano, (C₁-C₆)alkyl optionallysubstituted with from one to three fluorine atoms, (C₁-C₆)alkoxyoptionally substituted with from one to three fluorine atoms,(C₁-C₆)alkylsulfonyl, (C₁-C₆)acylamino, (phenyl)[(C₁-C₆)acyl]amino,amino, (C₁-C₆)alkylamino and di-(C₁-C₆)alkylamino;

[0015] with the proviso that when X³ is nitrogen, R² is absent;

[0016] (c) a compound of formula III:

[0017]  wherein each of the dotted lines represents an optional doublebond;

[0018] X is carbon or nitrogen;

[0019] R¹ is benzyl, aryl selected from phenyl, indanyl and naphthyl, orheteroaryl selected from pyridyl, thienyl, furyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl,wherein each of the foregoing aryl, heteroaryl and (C₁-C₄)alkyl groups,and the phenyl moiety of the benzyl group, may optionally be substitutedwith one or more substituents, preferably with from zero to twosubstituents, independently selected from halo (e.g., chloro, fluoro,bromo or iodo), (C₁-C₆)alkyl optionally substituted with from one tothree fluorine atoms, (C₁-C₆)alkoxy optionally substituted with from oneto three fluorine atoms, cyano, —C(═O)R⁸, aryl and heteroaryl, whereinsaid aryl is selected from phenyl, indanyl and naphthyl and saidheteroaryl is selected from pyridyl, thienyl, fiuyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;

[0020] R² and R³ are independently selected from hydrogen, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, —CONH₂ and —NHC(═O)R⁹, or R² and R³together form an oxo group;

[0021] R⁴ is hydrogen, sulfur, oxygen, (C₁-C₆)alkyl, amino, —NHR¹⁰,—SR¹⁰, OR¹⁰ or hydroxy;

[0022] R⁵, R⁶ and R⁷ are independently selected from hydrogen, halo(e.g., chloro, fluoro, bromo or iodo), cyano, (C₁-C₆)alkyl optionallysubstituted with from one to three fluorine atoms, (C₁-C₆)alkoxyoptionally substituted with from one to three fluorine atoms,(C₁-C₆)alkylsulfonyl, (C₁-C₆)acylamino, (phenyl)[(C₁-C₆)acyl]amino,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, aryl and heteroaryl,wherein said aryl is selected from phenyl, naphthyl and indanyl, andsaid heteroaryl is selected from pyridyl, thienyl, turyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl;

[0023] R⁸, R⁹ and R₁₀ are independently selected from hydrogen and(C₁-C₆)alkyl; and

[0024] R¹¹ is hydrogen, (C₁-C₆)alkyl or benzyl, wherein the phenylmoiety of said benzyl may optionally be substituted with one or moresubstituents, preferably with from zero to two substituents,independently selected from halo (e.g., fluoro, chloro, bromo, or iodo),(C₁-C₆)alkyl optionally substituted with from one to three fluorineatoms, (C₁-C₆)alkoxy optionally substituted with from one to threefluorine atoms, amino, cyano, (C₁-C₆)alkylamino anddi—(C₁-C₆)alkylamino;

[0025] with the proviso that: (a) R⁴ can not be either oxygen or hydroxywhen both R² and R³ are hydrogen; (b) when the five membered ring offormula I contains a double bond, R¹¹ is absent; (c) when R⁴ is sulfuiror oxygen, R⁴ is double bonded to the carbon to which is attached andsuch carbon is single bonded to both adjacent ring nitrogen atoms; and(d) when X is nitrogen and is double bonded to an adjacent carbon, R¹ isabsent;

[0026] (d) a compound of formula IV:

[0027]  and to pharmaceutically acceptable salts and solvates thereofwherein:

[0028] the dashed line in the above formula represents an optionaldouble bond where X² is not O;

[0029] X¹ and X² are each independently selected from O and —(CH₂)_(j)—wherein j is 1 or 2;

[0030] X³ is —CH(R⁵)N(R⁸)CH(R⁶)—, —CH(R⁵)C(R⁸)(R⁹)CH(R⁶)—,—C(R⁵)═C(R⁸)CH(R⁶)—, or —CH(R⁵)C(R⁸)═C(R⁶)—;

[0031] R¹ and R² are each independently H, hydroxy, or C₁-C₆ alkyl;

[0032] or R¹ and R² are taken together as a bond;

[0033] each R³ is independently selected from —S(O)_(j)R⁷ wherein j isan integer ranging from 0 to 2, —C(O)R⁷, —OR⁷, —NC(O)R⁷, —NR⁷R¹², andthe substituents provided in the definition of R⁷ other than H;

[0034] R⁴ is absent where the dashed line in the above formula 1represents a double bond or R⁴ is selected from H and the substituentsprovided in the definition of R³;

[0035] or R³ and R⁴ are taken together with the carbon atom to whicheach is attached to form a 5-10 membered mono-cyclic or bicyclic groupwherein said cyclic group may be carbocyclic or heterocyclic with 1 to 3heteroatoms selected from O, S, and —N(R¹¹)— with the proviso that two Oatoms, two S atoms, or an O and S atom are not attached directly to eachother; said cyclic group is saturated or partially unsaturated; aromaticor non-aromatic; 1 or 2 of the carbon atoms in said cyclic groupoptionally may be replaced by an oxo —C(O)— moiety; and said cyclicgroup is optionally substituted by 1 to 3 R¹⁰ groups;

[0036] R⁵ and R⁶ are each independently selected from H and C₁-C₄ alkyl;

[0037] or R⁵ and R⁶ are taken together as —(CH₂)_(q)— wherein q is 2 or3;

[0038] or R⁵ or R⁶ is taken together with R⁸ as defined below;

[0039] each R⁷ is independently selected from H, —(CH₂)_(t)(C₆-C₁₀ aryl)and —(CH₂)_(t)(4-10 membered heterocyclic), wherein t is an integerranging from 0 to 5; 1 or 2 of the carbon atoms of said heterocyclicgroup optionally may be replaced with an oxo —C(O)— group; said aryl andheterocyclic R⁷ groups are optionally fused to a benzene ring, a C₅-C₈saturated cyclic group, or a 4-10 membered heterocyclic group; the—(CH₂)_(t)— moieties of the foregoing R⁷ groups optionally include acarbon-carbon double or triple bond where t is an integer between 2 and5; and the foregoing R⁷ groups, except H, are optionally substituted by1 to 5 R¹⁰ groups;

[0040] R⁸ is selected from the substituents provided in the definitionof R⁷ other than H;

[0041] R⁹ is selected from the substituents provided in the definitionof R⁷;

[0042] or R⁸ and R⁹ are taken together with the carbon to which each isattached to form a 5-10 membered mono-cyclic or bicyclic group whereinsaid cyclic group is carbocyclic or heterocyclic with 1 to 3 heteroatomsselected from O, S, and —N(R¹¹)— with the proviso that two O atoms, twoS atoms, or an O and S atom are not attached directly to each other;saturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 ofthe carbon atoms in said cyclic group optionally may be replaced by anoxo —C(O)— moiety; and said cyclic group is optionally substituted by 1to 3 R¹⁰ groups;

[0043] or R⁸ taken together with either R⁵ or R⁶ and the separate carbonatoms to which each is attached to form a fused 5-10 memberedmono-cyclic or bicyclic group wherein said cyclic group may becarbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S,and —N(R¹¹)— with the proviso that two O atoms, two S atoms, or an O andS atom are not attached directly to each other; saturated or partiallyunsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms insaid cyclic group optionally may be replaced by an oxo —C(O)— moiety;and said cyclic group is optionally substituted by 1 to 3 R¹⁰ groups;

[0044] each R¹⁰ is independently selected from C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —R¹¹, —C(O)R¹¹, —C(O)OR¹¹, —NR¹²C(O)OR¹¹,—OC(O)R¹¹, —NR¹²SO₂R¹¹, —SO₂NR¹¹R¹², —NR¹²C(O)R¹¹, —C(O)NR¹¹, —NR¹¹R¹²,—S(O)_(j)(C₁-C₆ alkyl) wherein j is an integer ranging from 0 to 2,—(CH₂)_(m)(C₆-C₁₀ aryl), —SO₂(CH₂)_(m)(C₆-C₁₀ aryl), —S(CH₂)_(m)(C₆-C₁₀aryl), —O(CH₂)_(m)(C₆-C₁₀ aryl) and —(CH₂)_(m)(4-10 memberedheterocyclic), wherein m is an integer ranging from 0 to 4; said C₁-C₁₀alkyl group optionally contains 1 or 2 hetero moieties selected from O,S and —N(R¹²)— with the proviso that two O atoms, two S atoms, or an Oand S atom are not attached directly to each other; said aryl andheterocyclic R¹⁰ groups are optionally fused to a C₆-C₁₀ aryl group, aC₅-C₈ saturated cyclic group, or a 4-10 membered heterocyclic group; andsaid alkyl, aryl and heterocyclic R¹⁰ groups are optionally substitutedby 1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —NR¹²SO₂R¹¹, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹²C(O)R¹¹, —C(O)NR¹¹R¹², —NR¹¹R¹²,C₁-C₆ alkyl, —OR¹¹ and the substituents listed in the definition of R¹¹;

[0045] each R¹¹ is independently selected from H, C₁-C₁₀ alkyl,—(CH₂)_(m)(C₆-C₁₀ aryl), and —(CH₂)_(m)(4-10 membered heterocyclic),wherein m is an integer ranging from 0 to 4; said alkyl group optionallyincludes 1 or 2 hetero moieties selected from O, S and —N(R¹²)— with theproviso that two O atoms, two S atoms, or an O and S atom are notattached directly to each other; said aryl and heterocyclic R¹¹ groupsare optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclicgroup, or a 4-10 membered heterocyclic group; and the foregoing R¹¹subsituents, except H, are optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —C(O)R¹², —C(O)OR¹², —CO(O)R¹², —NR¹²C(O)R¹³,—C(O)NR¹²R³, —NR¹²R¹³, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; and,

[0046] each R¹² and R¹³ is independently H or C₁-C₆ alkyl;

[0047] (e) a compound of formula V:

[0048]  or the pharmaceutically acceptable salt thereof, wherein thebroken line represents an optional double bond;

[0049] a is 0 or 1, wherein when a is 0, X may form an optional doublebond with the carbon adjacent to V;

[0050] V is CHR¹⁰ wherein R¹⁰ is hydrogen or (C₁-C₆)alkyl;

[0051] T is nitrogen or CH;

[0052] X is nitrogen or CR¹¹ wherein R¹¹ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy or cyano;

[0053] Y and Z are each independently nitrogen or CR¹² wherein R¹² ishydrogen, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano,(C₁-C₆)alkoxy or (C₁-C₆)alkyl;

[0054] R¹is hydrogen, fluoro, chloro, bromo, trifluoromethyl,trifluoromethoxy, cyano or (C₁-C₆)alkyl;

[0055] R², R⁶, R⁷, R⁸ and R⁹ are each independently selected fromhydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,cyano, (C₁-C₆)alkoxy and (C₁-C₆)alkyl;

[0056] R³ and R⁴ are each independently hydrogen or (C₁-C₆)alkyl; and

[0057] R⁵ is hydrogen, (C₁-C₆)alkoxy, trifluoromethyl, cyano,(C₁-C₆)alkyl or R¹³CO— wherein R¹³ is amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkyl, (C₆-C₁₀)aryl;

[0058] or when a is 1, R¹ and R¹⁰may be taken together with the carbonsto which they are attached to form a compound of the formula

[0059]  wherein the broken lines represent optional bonds;

[0060] T, X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are defmed asabove;

[0061] b is 0 or 1; and

[0062] A and B are each independently CH, CH₂, oxygen, sulfur, NH ornitrogen;

[0063] with the proviso that when X is nitrogen, the optional doublebond between X and V does not exist;

[0064] with the proviso that when b is 0, the optional double bondbetween A and B does not exist; and with the proviso that when b is 1, Aand B cannot both be oxygen or sulfur;

[0065] or (f) a compound of formula VI:

[0066]  wherein a is oxygen, CH₂, C(CH₃)₂, NR¹⁰, sulfur, SO or SO₂;

[0067] b is oxygen, CH₂, C═O, C═NR¹¹, C═NOH, SO₂, sulfur, SO,C═NO(C₁-C₅)alkyl or CR⁷R⁸;

[0068] each of R¹ through R⁸ is selected, independently, from hydrogen,halogen (e.g., chloro, fluoro, bromo or iodo), trifluoromethyl, cyanoand hydroxy, or R⁷ and R⁸ together can be C(═O)NH₂ orC(═O)N(C₁-C₄)alkyl, with the proviso that neither R⁷ nor R⁸ can be halowhen a is oxygen, NR¹¹, sulfur, SO or SO₂; and

[0069] each of R¹⁰ and R¹¹ is selected, independently, from hydrogen,benzyl and (C₁-C₆)alkyl;

[0070] and the pharmaceutically acceptable salts of such compounds.

[0071] The term “one or more substituents”, as used herein, includesfrom one to the maximum number of substituents possible based on thenumber of available bonding sites.

[0072] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0073] The term “alkoxy”, as used herein, unless otherwise indicated,refers to radicals having the formula —O-alkyl, wherein “alkyl” isdefined as above.

[0074] In one embodiment this invention relates to a method of treatingor preventing a novelty-seeking disorder, comprising administering tothe subject an effective amount of a compound of formula I wherein

[0075] Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl,benzimidazolyl, or quinolyl; Ar¹ is phenyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or benzisoxazolyl; A is O, S, SO₂, C═O, CHOH, orCH₂; n is 0 or 1, wherein Ar and Ar¹ may be independently substitutedwith up to three substituents independently selected from the groupconsisting of fluoro, chloro, cyano, —NR¹R², —(C₁-C₆)alkoxy, —COOR,—CONR¹R², and —(C₁-C₆)alkyl and the pharmaceutically acceptable saltsthereof.

Embodiments of Formula I

[0076] In certain embodiments, this invention relates to a method oftreating or preventing a novelty-seeking, comprising administering tothe subject an effective amount of a compound of formula I wherein A isO or S; n is 1; Ar is phenyl or substituted phenyl, and thepharmaceutically acceptable salts thereof.

[0077] In other embodiments, this invention relates to a method oftreating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of a compound offormula I wherein A is CH₂; n is 0; Ar is benzoxazolonyl or substitutedbenzoxazolonyl; and the pharmaceutically acceptable salts thereof.; orwherein A is CH₂; n is 0; Ar is indolyl or substituted indolyl; and thepharmaceutically acceptable salts thereof; or wherein A is C═O or CHOH;n is 0 or 1; Ar is phenyl or substituted phenyl; and thepharmaceutically acceptable salt thereof; or wherein A is O; Ar isfluorophenyl, difluorophenyl or cyanophenyl; Ar¹ is chloropyridinyl; andthe pharmaceutically acceptable salt thereof; or wherein A is O; Ar isfluorophenyl, difluorophenyl or cyanophenyl; Ar¹ is fluoropyrimidinyl;and the pharmaceutically acceptable salt thereof; or wherein A is O; Aris fluorophenyl, difluorophenyl or cyanophenyl; Ar¹ is fluorophenyl; andthe pharmaceutically acceptable salt thereof; or wherein Ar¹ is5-chloro-pyridin-2-yl; and the pharmaceutically acceptable salt thereof;or wherein Ar¹ is 5-fluoro-pyrimidin-2-yl; and the pharmaceuticallyacceptable salts thereof.

[0078] In preferred embodiments of the method, A is O; S, SO, or SO₂;C═O or CHOH; CH₂; phenyl or substituted phenyl;

[0079] In other preferred embodiments of the method, Ar is naphthyl orsubstituted naphthyl; benzoxazolonyl or substituted benzoxazolonyl;indolyl or substituted indolyl; indolonyl or substituted indolonyl;benzimidazolyl or substituted benzimidazolyl; quinolyl or substitutedquinolyl.

[0080] In other preferred embodiments of the method, Ar¹ is phenyl orsubstituted phenyl; pyridinyl or substituted pyridinyl; pyridazinyl orsubstituted pyridazinyl; pyrimidinyl or substituted pyrimidinyl;pyrazinyl or substituted pyrazinyl; benzisoxazolyl or substitutedbenzisoxazolyl.

[0081] Specific preferred embodiments of the invention relate to amethod of treating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of the followingcompounds:

[0082](7R,9aS)-7-(4-fluorophenoxy)methyl-2-(5-chloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0083] (7R,9aS)-7-(3,5-difluorophenoxy)methyl-2-(5-chloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0084]3-[(7R,9aS)-2-(5-chloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-3H-benzoxazol-2-one;

[0085]3-[(7R,9aS)-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-3H-benzoxazol-2-one;

[0086] (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(5-fluoro-pyrimiidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0087](7R,9aS)-7-(3,5-difluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0088](7R,9aS)-7-(3,4-difluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0089] (7R,9aS)-7-(3-cyanophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0090] (7R,9aS)-7-(4-cyanophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0091](7R,9aS)-7-(4-iodophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0092](7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0093](7S,9aS)-7-(4-fluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0094](7S,9aS)-7-(2-carbomethoxy-4-fluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0095](7S,9aS)-7-(2-bromo-4-fluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0096](7S,9aS)-7-(4-fluoro-2-trifluoromethylphenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0097] (7S,9aS)-7-(3,5-difluorophenoxy)methyl-2-(5-chloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-appyrazine;

[0098](7S,9aS)-7-(4-fluorophenoxy)methyl-2-(5-chloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0099] (7S,9aS)-7-(2-chlorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0100](7S,9aS)-7-(4-fluoro-2-methylphenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;

[0101](7S,9aS)-7-(2,4-difluorophenoxy)methyl-2-(5-fluoro-pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine; and thepharmaceutically acceptable salt thereof.

Embodiments of Formula II

[0102] In preferred embodiments of the invention, compounds used in thepractice of the invention include those of the formula II, wherein R¹ isbromine and X² is nitrogen; or wherein R¹ is chlorine and X² isnitrogen.

[0103] Examples of specific compounds based on formula II used in thisinvention include the following:

[0104]1-[3-(4-pyridin-2-yl-piperazin-1-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0105]1-{3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;

[0106]1-{3-[4-(5-chloro-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;

[0107]1-{3-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoirnidazol-2-one;

[0108]1-[3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one; and

[0109]1-{3-[4-(6-chloro-pyridazin-3-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one.

[0110] Other embodiments of this invention include methods usingcompounds of the formula II wherein X² is carbon, X³ is nitrogen and R¹is hydrogen or substituted or unsubstituted alkoxy; or wherein X² and X³are both carbon and R¹ is hydrogen or substituted or unsubstitutedalkoxy; or wherein X¹ is carbon; or wherein X² and X³ are both carbonand each of R⁰, R¹ and R² is other than a fluoroalkyl group; or whereinX¹ is nitrogen.

[0111] Other embodiments of this invention include use of the followingcompounds of formula II:

[0112]1-[2-cyano-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0113]1-[5-methyl,3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0114]1-[6-cyano,3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0115] 1-{[3-[4-(5-fluoro-pyridin-2-yl]-propyl]-3-methyl-1,3-methyl-1,3-dihydro-benzoimidazol-2-one;

[0116]1-{[3-[4-(3-cyano-pyridin-2-yl)-piperazin-1-yl]-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0117]1-(3-[4-(4-cyano-pyridin-2-yl)-piperazin-1-yl]-propyl]-1,3-dihydro-benzoimidazol-2-one;

[0118]1-{3-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;

[0119] 1-{3-[4-(5-fluoro-pyridin-2-yl)-piperazin-1-yl]-propyl}-5-fluoro-1,3-dihydro-benzoimidazol-2-one; and

[0120]1-{3-[4-(5,fluoro-pyridin-2-yl)-piperazin-1-yl]-propyl}-5,6-difluoro-1,3-dihydro-benzoimidazol-2-one.

[0121] Preferred embodiments of the invention include a method oftreating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of any of the followingcompounds:

[0122]1-Benzoimidazol-1-yl-3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0123]1-(5-Chloro-benzoimidazol-1-yl)-3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0124]1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-5-trifluoromethyl-1H-benzoimidazole;

[0125]1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-1H-benzoimidazole;

[0126] 1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one;

[0127] 1-Benzoimidazol-1-yl-3-(4-o-tolyl-piperazine-1-yl)-propan-2-ol;

[0128] 1-Benzoimidazol-1-yl-3-(4-m-tolyl-piperazine-1-yl)-propan-2-ol;

[0129] 1-Benzoimidazol-1-yl-3-(4-p-tolyl-piperazin-1-yl)-propan-2-ol;

[0130] 1-Benzoimidazol-1-yl-3-{4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-propan-2-ol;

[0131]1-Benzoimidazol-1-yl-3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0132]1-Benzoimidazol-1-yl-3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0133]1-Benzoimidazol-1-yl-3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0134]1-Benzoimidazol-1-yl-3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0135]1-Benzoimidazol-1-yl-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propan-2-ol;

[0136]1-Benzoimidazol-1-yl-3-(4-naphthalen-1-yl-piperazin-1-yl)-propan-2-ol;

[0137]1-Benzoimidazol-1-yl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-2-ol;

[0138] 1-Benzoimidazol-1-yl-3-(4-benzyl-piperazin-1-yl)-propan-2-ol;

[0139]1-Benzoimidazol-1-yl-3-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-propan-2-ol;

[0140]1-Benzoimidazol-1-yl-3-[4-(2-ethoxy-benzyl)-piperazin-1-yl]-propan-2-ol;

[0141]1-Benzoimidazol-1-yl-3-{4-{3-(3-trifluoromethyl-phenyl)-propyl]-piperazin-1-yl}-propan-2-ol; and

[0142]1-Benzoimidazol-1-yl-3-{4-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-propan-2-ol;

[0143] Other preferred embodiments of the invention include a method oftreating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of any of the followingcompounds of formula II:

[0144](4-Chloro-2-nitro-phenyl)-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propyl}-amnine;

[0145] {3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-(2-nitro-4-trifluoromethyl-phenyl)-amine;

[0146]4-Chloro-N1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl}-propyl}-benzene-1,2-diamine;

[0147]1-(4,5-Dichloro-2-nitro-phenylamino)-3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0148]n1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-3-(2-phenyl-benzoimidazol-1-yl)-propan-2-ol;

[0149]1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-3-(2-propyl-benzoimidazol-1-yl)-propan-2-ol;

[0150]1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-3-(2-methyl-benzoimidazol-1-yl)-propan-2-ol;

[0151]5-Fluoro-1-(3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propyl)-2-methyl-1H-benzoimidazole;

[0152]5-Chloro-1-(3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl)-1,3-dihydro-benzoimidazol-2-one;

[0153]5-Fluoro-1-(3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-hydroxy-propyl)-1,3-dihydro-benzoimidazol-2-one;

[0154]1-Benzoimidazol-1-yl-3-[4-(3-methoxy-phenyl)-piperazin-1-yl]-propan-2-ol;

[0155]1-Benzoimidazol-1-yl-3-[4-(4-methoxy-phenyl)-piperazin-1-yl]propan-2-ol;

[0156] 1-Benzoimidazol-1-yl-3-(4-phenyl-piperazin-1-yl)-propan-2-ol;

[0157]1-{4-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-phenyl}-ethanone;

[0158]1-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-3-benzoimidazol-1-yl-propan-2-ol;

[0159]1-Benzoimidazol-1-yl-3-[4-(3,4-dimethyl-phenyl)-piperazin-1-yl]-propan-2-ol;

[0160]4-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-phenol;

[0161] 1-Benzoimidazol-1-yl-3-(4-phenethyl-piperazin-1-yl)-propan-2-ol;

[0162]1-Benzoimidazol-1-yl-3-[4-(3-phenyl-allyl)-piperazin-1-yl]propan-2-ol;

[0163]1-Benzoimidazol-1-yl-3-[4-(3-chloro-propyl)-piperazin-1-yl]-propan-2-ol;

[0164]2-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl-1-morpholin-4-yl-ethanone;

[0165] 1-(4-Benzhydryl-piperazin-1-yl)-3-benzoimidazol-1-yl-propan-2-ol;

[0166]1-Benzoimidazol-1-yl-3-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-propan-2-ol;

[0167]1-Benzoimidazol-1-yl-3-[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol;

[0168]4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazine-1-carboxylic;

[0169]5-Fluoro-1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propyl}-1H-benzoimidazole;

[0170]3-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-1-yl]-1-phenyl-propan-1-one;

[0171]4-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;

[0172]1-Benzoimidazol-1-yl-3-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]-propan-2-ol;

[0173][4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-(tetrahydro-furan-2-yl)-methanone;

[0174][4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone;

[0175][4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-(tetrahydro-furan-2-yl)-methanone;

[0176][4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanone;

[0177]1-Benzoimidazol-1-yl-3-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperazin-1-yl]-propan-2-ol;

[0178]1-Benzoimidazol-1-yl-3-[4-2-nitro-butyl)-piperazin-1-yl]-propan-2-ol;

[0179]3-[4-(3-Benzoimidazol-1-yl-2-hydroxy-propyl)-piperazin-1-yl]-1-(4-chloro-phenyl)-propan-1-one;

[0180]1-Benzoimidazol-1-yl-3-[4-(5,5-diphenyl-pent-3-phenyl)-piperazin-1-yl]-propan-2-ol;

[0181]1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-3-(2-phenyl-benzoimidazol-1-yl)-propan-2-ol;

[0182]5,6-Difluoro-1-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propyl}-1H-benzoimidazol;and

[0183]1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-3-(2-propyl-benzoimidazol-1-yl)-propan-2-ol.

Embodiments of Formula III

[0184] Other embodiments of this invention include a method of treatingor preventing a novelty-seeking disorder, comprising administering tothe subject an effective amount of any of the following compounds:

[0185] (a) compounds of formula III wherein R¹ is phenyl and is eitherunsubstituted or substituted with one or two substituents selected fromhalo, (C₁-C₆)alkyl substituted with from one to three fluorine atoms,(C₁-C₆)alkoxy substituted with from one to three fluorine atoms, cyano,—C(═O)R⁸, aryl and heteroaryl;

[0186] (b) compounds of formula III wherein R¹ is indanyl and is eitherunsubstituted or substituted with one or two substituents selected fromhalo, (C₁-C₆)alkyl substituted with from one to three fluorine atoms,(C₁-C₆)alkoxy substituted with from one to three fluorine atoms, cyano,—C(═O)R⁸, aryl and heteroaryl;

[0187] (c) compounds of formula III wherein R¹ is naphthyl and is eitherunsubstituted or substituted with one or two substituents selected fromhalo, (C₁-C₆)alkyl substituted with from one to three fluorine atoms,(C₁-C₆)alkoxy substituted with from one to three fluorine atoms, cyano,—C(═O)R⁸, aryl and heteroaryl;

[0188] (d) compounds of formula III wherein R¹ is heteroaryl and iseither unsubstituted or substituted with one or two substituentsselected from halo, (C₁-C₆)alkyl substituted with from one to threefluorine atoms, (C₁-C₆)alkoxy substituted with from one to threefluorine atoms, cyano, —C(═O)R⁸, aryl and heteroaryl;

[0189] (e) compounds of formula III wherein R⁵, R⁶ and R⁷ areindependently selected from (C₁-C₆)alkyl optionally substituted withfrom one to three fluorine atoms, (C₁-C₆)alkoxy optionally substitutedwith from one to three fluorine atoms, cyano and halo;

[0190] (f) compounds of formula III wherein R⁴ is hydrogen;

[0191] (g) compounds of formula III wherein R⁴ is (C₁-C₆)alkyl;

[0192] (h) compounds of formula III wherein R⁴ is amino;

[0193] (i) compounds of formula III wherein R⁴ is —NHR¹⁰;

[0194] (j) compounds of formula III wherein R⁴ is SR¹⁰;

[0195] (k) compounds of formula III wherein R⁴ is —OR¹⁰;

[0196] (l) compounds of formula III wherein R⁴ is hydroxy;

[0197] (m) compounds of formula III wherein R¹¹ is absent;

[0198] (n) compounds of formula III wherein R² and R³ are both hydrogen;

[0199] (o) compounds of formula III wherein one or both of R² and R³ arehydroxy;

[0200] (p) compounds of formula III wherein R² and R³ together form anoxo group;

[0201] (q) compounds of formula III wherein one of R² and R³ is(C₁-C₆)alkyl;

[0202] (r) compounds of formula III wherein X is carbon;

[0203] (s) compounds of formula III wherein X is nitrogen;

[0204] (t) compounds of formula III wherein R⁴ is oxygen; and

[0205] (v) compounds of formula III wherein R⁴ is sulfur.

Emodiments of Formula IV

[0206] Certain embodiments of the invention include a method of treatingor preventing a novelty-seeking disorder, comprising administering tothe subject an effective amount of compounds of formula IV having thefollowing structure

[0207] wherein R³ is —(CH₂)_(t)(C₆-C₁₀ aryl) or —(CH₂)_(t)(4-10 memberedheterocyclic), R⁴ is H or hydroxy, and R⁸ is —(CH₂)_(t)(C₆-C₁₀ aryl) or—(CH₂)_(t)(4-10 membered heterocyclic), t is an integer ranging from 0to 5, and the foregoing R³ and R⁸ heterocyclic groups are optionallyfused to a benzene ring, and said R³ and R⁸ groups are optionallysubstituted by 1 to 3 R¹⁰ groups. More specific embodiments include useof those compounds wherein R⁸ and R³ are each independently selectedfrom phenyl and pyrimidyl, optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, methoxy, trifluoromethyl,methanesulfonyl, amino, trifluoromethoxy, acetamido, and C₁-C₆ alkyl.Other more specific embodiments include those wherein R³ is aheterocyclic group fused to a benzene ring and, optionally, 1 or 2 ofthe carbon atoms of said heterocyclic group is replaced with an oxo—C(O)— group. In particular, such specific embodiments of the inventionuse compounds wherein R³ comprises the following groups:

[0208] wherein the benzo portion of the above R³ groups is optionallysubstituted by 1 to 3 R¹⁰ groups

[0209] Other embodiments of the invention include a method of treatingor preventing a novelty-seeking disorder, comprising administering tothe subject an effective amount of any compound of formula IV having thefollowing structure

[0210] wherein R³ is —O(CH₂)_(t)(C₆-C₁₀ aryl) or —O(CH₂)_(t)(4-10membered heterocyclic), R⁴ is H or hydroxy, and R⁸ is —(CH₂)_(t)(C₆-C₁₀aryl) or —(CH₂)_(t)(4-10 membered heterocyclic), wherein t is an integerranging from 0 to 5, and wherein the foregoing R³ and R⁸ groups areoptionally substituted by 1 to 3 R¹⁰ groups. More specific embodimentsof the invention include the described method wherein R³ is phenoxy andR⁸ is phenyl or pyrimidyl, and said R³ and R⁸ groups are optionallysubstituted by 1 to 3 substituents independently selected from halo,cyano, methoxy, trifluoromethyl, methanesulfonyl, amino,trifluoromethoxy, acetamido, and C₁-C₆ alkyl.

[0211] Other embodiments of the invention include a method of treatingor preventing a novelty-seeking disorder, comprising administering tothe subject an effective amount of any compound: of formula IV havingthe following structure

[0212] wherein R³ and R⁴ are taken together with the carbon atom towhich each is attached to form a 5-10 membered mono-cyclic or bicyclicgroup wherein said cyclic group may be carbocyclic or heterocyclic with1 to 3 heteroatoms selected from O, S, and —N(R¹¹)— with the provisothat two O atoms, two S atoms, or an O and S atom are not attacheddirectly to each other; said cyclic group is saturated or partiallyunsaturated; aromatic or non-aromatic; 1 or 2 of the carbon atoms insaid cyclic group optionally may be replaced by an oxo —C(O)— moiety;and said cyclic group is optionally substituted by 1 to 3 R¹⁰ groups;and R⁸ is —(CH₂)_(t)(C₆-C₁₀ aryl) or —(CH₂)_(t)(4-10 memberedheterocyclic), wherein t is an integer ranging from 0 to 5 and said R⁸group is optionally substituted by 1 to 3 R¹⁰ groups. More specificembodiments of the invention include the described method wherein R⁸ isphenyl or pyrimidyl, and R³ and R⁴ are taken together to form a groupselected from and

[0213] and said R⁸, R³ and R⁴ groups are optionally substituted by 1 to3 substituents independently selected from halo, cyano, methoxy,trifluoromethyl, methanesulfonyl, amino, trifluoromethoxy, acetamido,and C₁-C₆ alkyl.

[0214] Specific embodiments of the invention include a method oftreating or preventing a novelty-seeking, comprising administering tothe subject an effective amount of any of the following compounds offormula IV:

[0215](2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2′-one;

[0216](2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2′-phenyl-octahydro-pentalen-2′ol,maleate salt;

[0217] (2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one, ethylene ketal;

[0218] (2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one;

[0219](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-hydroxy-5′-phenyl-octahydro-pentalen-2′-yl)-pipeerazin-1-yl]-benzonitrile,maleate salt;

[0220] (2α,3aβ,5α,6aβ)-5-Hydroxy-5-phenyl-hexahydro-pentalen-2-one;

[0221](2′α,3′aβ,5′α,6′aβ)-5′-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2′-phenyl-octahydro-pentalen-2′ol,maleate salt;

[0222](2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-1-pyrimidyl)-piperazin-1-yl]-2′-(4flouro-phenyl)-octahydro-pentalen-2′ol, maleate salt;

[0223](2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-2′-(4-fluoro-phenyl)-octahydro-pentalen-2′ol, maleate salt;

[0224](2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2′-(4-fluoro-phenyl)-octahydro-pentalen-2′ol,maleate salt;

[0225] (2′α,3′aβ,6′aβ)-1-(4-Fluoro-phenyl)-4-(5′-phenyl -1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen -2′-yl)-piperazine dihydrochloride;

[0226] (2′α,3′aβ,6′aβ)-5-Fluoro-2-[4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine maleate;

[0227] (2′α,3′aβ,6′aβ)-2-Fluoro-4-[4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;

[0228] (2′α,3′aβ,6′aβ)-2-Fluoro-4-{4-[5-(2-methoxy-phenyl)-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0229] (2′α,3′aβ,6′aβ)-1-Phenyl-4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentaleno-2′-yl)-piperazine, dimaleate;

[0230](2′α,3′aβ,5′α,6′aβ)-1-(4-Fluoro-phenyl)-4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazine,dihydrochloride;

[0231] (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine, maleate;

[0232] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;

[0233] (2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazine, maleate;

[0234](2′α,3′aβ,5′α,6′aβ)-5′-Hydroxy-5′-(2-trifluoromethyl-phenyl)-hexahydro-pentalen-2′-one;

[0235](2′α,3′aβ,6′aβ)-5′-(2-trifluoromethyl-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2′-one, ethylene ketal;

[0236](2′α,3′aβ,5′α,6′aβ)-5′-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2′-one, ethylene ketal;

[0237](2′α,3′aβ,5′α,6′aβ)-5′-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2′-one;

[0238](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-trifluoromethyl-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0239](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0240](2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-{4-[5′-(2-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-pyrimidine,maleate;

[0241](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(3-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0242](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(4-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0243](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile,maleate;

[0244](2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine,maleate;

[0245](2′α,3′aβ,5′α,6′aβ)-5-Chloro-2-{4-[5′-(2-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-pyrimidine,maleate;

[0246](2′α,3′aβ,5′α,6′aβ)-5-Chloro-2-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine,maleate;

[0247](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-methanesulfonyl-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0248] (2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-[5′-(3-pyrrolidin-1-ylmethyl-phenyl)-octahydro-pentalen-2′-yl]-piperazine, dimaleate;

[0249] 5-Trimethylstannayl-3,3a,4,6a-tetrahydro-1H-pentalen-2-one,ethylene ketal;

[0250] 5-(2-Cyano-phenyl)-3,3 a,4,6a-tetrahydro-1H-pentalen-2-one;

[0251](2′α,3′aβ,5′α,6′aβ)-2-Cyano-4-{4-[5′-(2-fluoro-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0252](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-trifluoromethoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0253](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-fluoro-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0254] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-pyridin-2-yl-octahydro-pentalen-2′-piperazin-1-yl]-benzonitrile,dihydrochloride;

[0255](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-m-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile,maleate;

[0256] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-p-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;

[0257] (2′α,3′aβ,5′α,6′aβ)-N-(2-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-phenyl)-acetamide,maleate;

[0258](2′α,3′aβ,5′α,6′aβ)-N-(2-{5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1yl]-octahydro-pentalen-2′-yl}-phenyl)-acetamide,maleate;

[0259] 5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one,ethylene ketal;

[0260] 2-(5-Oxo-octahydro-pentalen-2-yl)-benzamide, ethylene ketal;

[0261] (2′α,3′aβ,5′α,6′aβ)-2-{5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-benzamide,maleate;

[0262](2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3′,3′a,4′,5′,6′,6′a-hexaydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate;

[0263] (2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzo-nitrile,maleate;

[0264] (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-piperazin-1-yl]-pyrimidine;

[0265] (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-piperazin-1-yl]-pyrim-idine;

[0266] (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-dimethylspiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-pyrimidine, maleate;

[0267] (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6a-hexahydro-3′a,6′a-dimethylspiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-pyrimidine, maleate;

[0268] (2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate;

[0269] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate;

[0270] (2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-piperazine,maleate;

[0271] (2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-piperazine,maleate;

[0272] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-1-piperazinyl]-benzonitrile,maleate;

[0273] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-1-piperazinyl]-benzonitrile,maleate;

[0274] (2′α,3′aβ,5′α,6′aβ)-5-Benzylamino-hexahydropentalen-2-one,mono-ethylene ketal;

[0275] (2′α,3′aβ,5′α,6′aβ)-5-Amino-hexahydropentalen-2-one,mono-ethylene ketal;

[0276](2′α,3′aβ,5′α,6′aβ)-5-(5-Fluoro-2-nitro-phenylamino)-hexahydropentalen-2-one,mono-ethylene ketal;

[0277](2′α,3′aβ,5′α,6′aβ)-5-(2-Amino-5-fluoro-phenylamino)-hexahydropentalen-2-one,mono-ethylene ketal;

[0278] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(6-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,dimesylate;

[0279] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,mesylate;

[0280](2′α,3′aβ,5′α,6′aβ)-1-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one,mesylate;

[0281](2′α,3′aβ,5′α,6′aβ)-5-(6-Fluoro-2-methyl-benzoimidazol-1-yl)-hexahydro-pentalen-2-one;

[0282] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(6-fluoro-2-methylbenzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,dimesylate;

[0283](2′α,3′aβ,5′α,6′aβ)-6-Fluoro-2-methyl-1-[5′-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]-1H-benzoimidazole, dimaleate;

[0284](2′α,3′aβ,6′aβ)-5-(1H-Indol-3-yl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one,mono-ethylene ketal;

[0285] (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(1H-indol-3-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl }-benzonitrile, maleate;

[0286](2′α,3′aβ,5′α,6′aβ)-3-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]1H-indole,maleate;

[0287](2′α,3′aβ,5′α,6′aβ)-5-(4-Fluoro-phenoxy)-hexahydro-pentalen-2-one;

[0288] (2′α,3′aβ,5′β,6′aβ)-1-[5′-(4-Fluoro-phenoxy)-octahydro-pentalen-2′-yl]-4-phenyl-piperazine, maleate;

[0289](2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-{4-[5′-(4-fluoro-phenoxy)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;

[0290](2′α,3′aβ,5′β,6′aβ)-5-Fluoro-2-{4-[5′-(4-fluoro-phenoxy)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-pyrimidine,maleate;

[0291] (2′α,3′aβ,5′β,6′aβ)-1-[5′-(4-Fluoro-phenoxy)-octahydro-pentalen-2′-yl]-4-phenyl-piperazine, maleate;

[0292](2′α,3′aβ,5′β,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]-isoindole-1,3-dione maleate;

[0293] (2′α,3′aβ,5′α,6′aβ)-5-Hydroxy-hexahydro-pentalen-2-one, ethyleneketal;

[0294] (2′α,3′aβ,5′α,6′aβ)-2-Oxo-3-(5-oxo-octahydro-pentalen-2-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester, ethyleneketal;

[0295](2′α,3′aβ,5′α,6′aβ)-2-(5-oxo-octahydro-pentalen-2-yloxy)-3H-benzoimidazole-1-carboxylic acid tert-butyl ester, ethylene ketal;

[0296] (2′α,3′aβ,5′α,6′aβ)-3-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylicacid tert-butyl ester;

[0297](2′α,3′aβ,5′α,6′aβ)-1-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one, maleate;

[0298](2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-{4-[5′-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile, maleate;

[0299](2′α,3′aβ,5′α,6′aβ)-1-{5′-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one, maleate;

[0300] (2′α,3′aβ,5′α,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yloxy]-1H-benzoimidazole, maleate;

[0301] (2′α,3′aβ,5′α,6′aβ)-2-(5-Oxo-octahydro-pentalen-2-yl)-isoindole-1,3-dione;

[0302] (2′α,3′aβ,5′β,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-isoindole-1,3-dione, maleate;

[0303](2′α,3′aβ,5′β,6′aβ)-4-{4-[5′-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-2-fluoro-benzonitrile, maleate;

[0304] (2′α,3′aβ,5′β,6′aβ)-2-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione,maleate;

[0305] (2′α,3′aβ,5′α,6′aβ)-2-{5′-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione, maleate;

[0306] (2′α,3′aβ,5′α,6′aβ)-2-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione, maleate; and,

[0307](2′α,3′aβ,5′α,6′aβ)-N-[5-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2-yl]-benzamide,maleate.

Embodiments of Formula V

[0308] Preferred embodiments of the invention include a method oftreating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of the compound offormula V wherein X is nitrogen; or wherein Y and Z are each CR¹²wherein R¹² is hydrogen or fluoro; or wherein R² is hydrogen, fluoro orchloro; or wherein R³, R⁴ and R⁵ are hydrogen; or wherein R⁷ is fluoroor chloro; or wherein R⁹ is fluoro, chloro, bromo or alkoxy; or, morespecifically, wherein X is nitrogen; Y and Z are each CR¹³ wherein R¹³is hydrogen or fluoro; R² is hydrogen fluoro or chloro; R³, R⁴ and R⁵are hydrogen; R⁷ is fluoro or chloro; and R⁹ is fluoro, chloro, bromo oralkoxy.

[0309] Specific preferred embodiments of the invention include a methodof treating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of any of the followingcompounds of formula V:

[0310] 2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

[0311]5-Fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

[0312] 5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin 1-ylmethyl]-1H-indole;

[0313] 5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole;

[0314] 5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;

[0315]2-[4-(6-Chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole;

[0316]5-Fluoro-2-(4-[5′-fluoro]pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;

[0317] 2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole;

[0318] 5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole;and

[0319] 2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-azaindole.

Embodiments of Formula VI

[0320] Preferred embodiments of the invention include a method oftreating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of any of the compoundsof formula VI wherein a is oxygen, b is CH₂, each of R¹, R⁴ and R⁵ ishydrogen, and each of R², R³ and R⁶ is selected, independently fromhydrogen, cyano, chloro and fluoro.

[0321] Other more specific embodiments of this invention include amethod of treating or preventing a novelty-seeking disorder, comprisingadministering to the subject an effective amount of any of the followingcompounds:

[0322] (a) compounds of formula VI wherein a is oxygen;

[0323] (b) compounds of formula VI wherein a is oxygen and b is CH₂;

[0324] (c) compounds of formula VI wherein a is oxygen, b is CH₂ andeach of R¹, R⁴ and R⁵ is hydrogen;

[0325] (d) compounds of formula VI wherein a is oxygen, b is CH₂, eachof R¹, R⁴ and R⁵ is hydrogen and R³ is fluoro, cyano or chloro;

[0326] (e) compounds of formula VI wherein a is oxygen, b is CH₂, eachof R¹, R⁴ and R⁵ is hydrogen and each of R², R³ and R⁶ is selected,independently, from hydrogen, fluoro, cyano and chloro; and

[0327] (f) compounds of formula VI wherein a is oxygen, b is CH₂, eachof R¹, R⁴ and R⁵ is hydrogen, and R² and R³ are selected, independently,from fluoro, cyano and chloro.

[0328] The compounds of formula I, II, III, IV, V and VI above maycontain chiral centers and therefore may exist in different enantiomericforms. This invention relates to a method of treating or preventing anovelty-seeking disorder, comprising administering to the subject aneffective amount of any of the optical isomers and all otherstereoisomers of compounds of the formula I, II, III, IV, V and VI andmixtures thereof.

[0329] The compounds of formula I, II, III, IV, V and VI that are basicin nature are capable of forming a wide variety of salts with variousinorganic and organic acids. The acids that may be used to preparepharmaceutically acceptable acid addition salts are those that formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,acetate, lactate, salicylate, citrate, acid citrate, tartrate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0330] Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a compound of the formula I, II, III, IV, V and VIfrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent and subsequently convert the latterfree base to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the basic compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isreadily obtained. The desired acid salt can also be precipitated from asolution of the free base in an organic solvent by adding to thesolution an appropriate mineral or organic acid.

[0331] The novel compounds of the formula I, II, III, IV, V and VI andthe pharmaceutically acceptable salts thereof (herein referred to as“the therapeutic compounds of this invention”) are useful as dopamine D4receptor ligands, i.e., they possess the ability to inhibit the bindingof dopamine D4 ligands to the dopamine D4 receptor in various subjects,including humans. They and other dopamine D4 receptor ligands aretherefore able to function as therapeutic agents in the treatment orprevention of a variety of conditions in subjects, including humans, thetreatment or prevention of which can be effected or facilitated by adecrease in binding of doparnine D4 receptor ligands with the dopamineD4 receptor, including a novelty-seeking disorder selected frompathological gambling, attention deficit disorder with hyperactivitydisorder (ADHD), substance addiction (e.g., drug addiction and alcoholaddiction) and sex addiction.

[0332] The term “dopaminergic effective amount”, as used herein, refersto an amount sufficient to inhibit the binding of dopamine to a dopaminereceptor.

[0333] The term “altering dopamine mediated neurotransmission”, as usedherein, includes but is not limited to increasing or decreasing D4dopamine receptor mediated neurotransmission.

[0334] The term “novelty seeking disorder”, as used herein, refers to amaladaptive variant of the personality trait of seeking novelty in thedimensional model of personality disorders. See DSM-IV. Examples ofnovelty-seeking disorders include: pathological gambling, attentiondeficit disorder with hyperactivity disorder (ADHD), substance addiction(e.g., drug addiction and alcohol addiction) and sex addiction.

DETAILED DESCRIPTION OF THE INVENTION

[0335] The compounds of the formula I, II, III, IV, V and VI may beprepared as described below. Unless otherwise indicated in thediscussion that follows, structural formulae I, II, III, IV and V aredefined as above.

[0336] Compounds of the formula I may be prepared as decribed in U.S.Pat. No. 5,852,031, issued Dec. 22, 1998. This patent is incorporatedherein by reference in its entirety.

[0337] Compounds of the formula II may be prepared as described in U.S.Pat. No. 5,883,094, issued Mar. 16, 1999. This patent is incorporatedherein by reference in its entirety.

[0338] Compounds of the formula III may be prepared as described in U.S.Pat. No. 5,889,010, issued Mar. 30, 1999. This patent is incorporatedherein by reference in its entirety.

[0339] Compounds of the formula IV may be prepared as described in U.S.patent application Ser. No. 09/300,262, filed Apr. 27, 1999. Thisapplication is incorporated herein by reference in its entirety.

[0340] Compounds of the formula V may be prepared as described in PCTInternational Application No. PCT/IB98/01198 and designates the UnitedStates, and was published as Publication No. published as WO99/09025 onFeb. 25, 1999. This application is incorporated herein by reference inits entirety.

[0341] Compounds of the formula VI may be prepared as described in PCTInternational Application No. PCT/IB97/00978, which was filed in theInternational Bureau on Aug. 8, 1997 and designates the United States,and was published as Publication No. WO98/08835 on Mar. 5, 1998. Thisapplication is incorporated herein by reference in its entirety.

[0342] The compounds of the formula I, II, III, IV, V and VI, hereinreferenced to collectively as the “therapeutic agents” and thepharmaceutically acceptable salts thereof, are useful as dopamine D4receptor ligands. Other dopamine D4 receptor ligands that may be used inaccordance with the methods of this invention are the compounds andpharmaceutically acceptable salts thereof described in the followingreferences: U.S. patent application Ser. No. 5,877,317 issued on Mar. 2,1999; U.S. patent application Ser. No. 5,021,420, issued on Jun. 4,1991; U.S. patent application Ser. No. 5,633,376, issued on May 27,1997; U.S. patent application, Ser. No. 5,432,177, issued on Nov. 9,1994; U.S. patent application Ser. No. 5,622,950, issued on Apr. 22,1997, PCT International Application No. PCT/EP93/01438, published asWO94/00458 on Jan. 6, 1994; U.S. patent application Ser. No. 5,998,414,issued on Dec. 7, 1999; U.S. patent application Ser. No. 5,968,478,issued on Oct. 19, 1999; U.S. patent application Ser. No. 6,040,448,issued on Mar. 21, 2000; U.S. patent application Ser. No. 6,051,605,issued on Apr. 18, 2000; U.S. patent application Ser. No. 5,945,421,issued on Aug. 31, 1999; and U.S. patent application Ser. No. 5,798,350,issued on Aug. 25, 1998. Each of the foregoing patents and patentpublications is incorporated herein by reference in its entirety.

[0343] The therapeutic compounds used in this invention can beadministered orally, transdermally (e.g., through the use of a patch),parenterally or topically. Oral administration is preferred. In general,these compounds are most desirably administered in dosages ranging fromabout 0.1 mg up to about 1000 mg per day, or 1 mg to 1000 mg per day insome cases, although variations may occur depending on the weight andcondition of the person being treated and the particular route ofadministration chosen. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, provided that such larger doses are first divided intoseveral small doses for administration throughout the day.

[0344] The therapeutic compounds used in the invention may beadministered alone or in combination with pharmaceutically acceptablecarriers or diluents by either of the two routes previously indicated,and such administration may be carried out in single or multiple doses.More particularly, the novel therapeutic compounds of this invention canbe administered in a wide variety of different dosage forms, i.e., theymay be combined with various pharmaceutically acceptable inert carriersin the form of tablets, capsules, lozenges, troches, hard candies,powders, sprays, creams, salves, suppositories, jellies, gels, pastes,lotions, ointments, elixirs, syrups, and the like. Such carriers includesolid diluents or fillers, sterile aqueous media and various non-toxicorganic solvents, for example. Moreover, oral pharmaceuticalcompositions can be suitably sweetened and/or flavored.

[0345] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tabletingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0346] For parenteral administration, solutions of a therapeuticcompound used in the present invention in either sesame or peanut oil orin aqueous propylene glycol may be employed. The aqueous solutionsshould be suitably buffered if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

[0347] Additionally, it is also possible to administer the compoundsused in the present invention topically when treating inflammatoryconditions of the skin and this may preferably be done by way of creams,jellies, gels, pastes, ointments and the like, in accordance withstandard pharmaceutical practice.

[0348] Dopaminergic activity of the compounds used in the invention isrelated to the ability of the compounds to bind to the D₄ receptors, andthe relative ability of compounds of this invention to inhibit[³H]-spiperone binding to human dopamine D₄ receptor subtypes expressedin clonal cell lines was measured using the following procedure.

[0349] The determination of D₄ receptor binding ability has beendescribed by Van Tol et al., Nature, 350, 610 (1991)). Clonal cell linesexpressing the human dopamine D₄ receptor are harvested and homogenized(polytron) in a 50 mM Tris:HCl (pH 7.4 at 4° C.) buffer containing 5 mMEDTA, 1.5 mM calcium chloride (CaCl₂), 5 mM magnesium chloride (MgCl₂),5 mM potassium chloride (KCl) and 120 mM sodium chloride (NaCl). Thehomogenates are centrifugated for 10-15 min. at 48,000 g, and theresulting pellets resuspended in a buffer at a concentration of 150-250mg/ml. For saturation experiments, 0.75 ml aliquots of tissue homogenateare incubated in triplicate with increasing concentrations of [³H]spiperone (70.3 Ci/mmol; 10-3000 pM final concentration) for 30-120minutes at 22° C. in a total volume of 1 ml. For competition bindingexperiments, assays are initiated by the addition of 0.75 ml of membraneand incubated in duplicate with the indicated concentrations ofcompeting ligands (10⁻¹⁴-10⁻³ M) and/or [³H]spiperone (100-300 pM) for60-120 min at 22° C. Assays are terminated by rapid filtration through aBrandell cell harvester and the filters subsequently monitored fortritium as described by Sunahara, R. K. et al., Nature, 346, 76-80(1990). For all experiments, specific [³H]spiperone binding is definedas that inhibited by 1-10 mM (+)-butaclamol. Binding data are analyzedby non-linear least squares curve-fitting. All of the compounds recitedherein which were tested in this assay were found to have bindingaffinities (K_(i)) for the displacement of [³H]-spiperone of less than 2micromolar.

[0350] Utility of the present invention may be determined for therecited dopamine D4 ligands by administering any of the ligands tosubjects deemed to be suffering from a novelty-seeking disorder asdetermined from a Temperament and Character Inventory (Cloninger et al,Arch. Gen. Psychiatry, 50, 975-990 (1993)) and comparing the NoveltySeeking scores prior to and after the administration of the ligand. (SeeMalhotra et al., Mol. Psychiatry, 1, 388-391 (1996)). An improvedNovelty Seeking score indicates an effective ligand dosage foradministration to a subject in need of treatment.

What is claimed is:
 1. A method of treating or preventing anovelty-seeking disorder in a subject comprising administering to thesubject: (a) an amount of a compound having the formula:

 wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl,benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl,oxazolyl, benzoxazolyl; Ar¹ is phenyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, or benzisothiazolyl; A is O, S,SO, SO₂, C═O, CHOH, or —(CR³R⁴)—; n is 0, 1 or 2; each of Ar and Ar¹ maybe independently and optionally substituted with one to foursubstituents independently selected from the groups consisting offluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO₂R,—NHSO₂R, —(C₁-C₆)alkoxy, —NR¹R², —NRCOR¹, —CONR¹R², Ph, —COR, COOR,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted with one to six halogens,—(C₃-C₆)cycloalkyl, and trifluoromethoxy; each and every R, R¹, and R²is independently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl substituted with one to thirteen halogensselected from fluorine, chlorine, bromine and iodine, phenyl, benzyl,—(C₂-C₆)alkenyl, —(C₃-C₆)cycloalkyl, and —(C₁-C₆)alkoxy; each and everyR³ and R⁴ is independently selected from a group consisting of hydrogen,methyl, ethyl, n-propyl, and i-propyl; diastereomeric and opticalisomers thereof; and pharmaceutically acceptable salts thereof; (b) anamount of a compound of the formula

 wherein X¹, X² and X³ are independently selected from carbon andnitrogen; R⁰, R¹ and R² are independently selected from hydrogen, halo(e.g., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionallysubstituted with from one to three fluorine atoms and (C₁-C₆)alkoxyoptionally substituted with from one to three fluorine atoms; R³ ishydrogen, (C₁-C₆)alkyl or benzyl, wherein the phenyl moiety of saidbenzyl group may optionally be substituted with from one or moresubstituents, independently selected from halo, cyano, (C₁-C₆)alkyloptionally substituted with from one to three fluorine atoms,(C₁-C₆)alkoxy optionally substituted with from one to three fluorineatoms, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylamino, amino,di-(C₁-C₆)alkylamino and (C₁-C₆)carboxamido; R⁴, R⁵ and R⁶ areindependently selected from hydrogen, halo (e.g., chloro, fluoro, bromoand iodo), cyano, (C₁-C₆)alkyl optionally substituted with from one tothree fluorine atoms, (C₁-C₆)alkoxy optionally substituted with from oneto three fluorine atoms, (C₁-C₆)alkylsulfonyl, (C₁-C₆)acylamino,(phenyl)[(C₁-C₆)acyl]amino, amino, (C₁-C₆)alkylamino anddi-(C₁-C₆)alkylamino; with the proviso that when X³ is nitrogen, R² isabsent; or a pharmaceutically acceptable salt thereof; (c) an amount ofa compound of the formula

 wherein each of the dotted lines represents an optional double bond; Xis carbon or nitrogen; R¹ is benzyl, aryl selected from phenyl, indanyland naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl andimidazolyl, wherein each of the foregoing aryl, heteroaryl and(C₁-C₄)alkyl groups, and the phenyl moiety of the benzyl group, mayoptionally be substituted with one or more substituents, preferably withfrom zero to two substituents, independently selected from halo (e.g.,chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionally substituted withfrom one to three fluorine atoms, (C₁-C₆)alkoxy optionally substitutedwith from one to three fluorine atoms, cyano, —C(═O)R⁸, aryl andheteroaryl, wherein said aryl is selected from phenyl, indanyl andnaphthyl and said heteroaryl is selected from pyridyl, thienyl, furyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl andimidazolyl; R² and R³ are independently selected from hydrogen, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, cyano, —CONH₂ and —NHC(═O)R⁹, or R² and R³together form an oxo group; R⁴ is hydrogen, sulfur, oxygen,(C₁-C₆)alkyl, amino, —NHR¹⁰, —SR¹⁰, OR¹⁰ or hydroxy; R⁵, R⁶ and R⁷ areindependently selected from hydrogen, halo (e.g., chloro, fluoro, bromoor iodo), cyano, (C₁-C₆)alkyl optionally substituted with from one tothree fluorine atoms, (C₁-C₆)alkoxy optionally substituted with from oneto three fluorine atoms, (C₁-C₆)alkylsulfonyl, (C₁-C₆)acylamino,(phenyl)[(C₁-C₆)acyl]amino, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, aryl and heteroaryl, wherein said aryl is selectedfrom phenyl, naphthyl and indanyl, and said heteroaryl is selected frompyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, quinolyl and imidazolyl; R⁸, R⁹ and R¹⁰ are independentlyselected from hydrogen and (C₁-C₆)alkyl; and R¹¹ is hydrogen,(C₁-C₆)alkyl or benzyl, wherein the phenyl moiety of said benzyl mayoptionally be substituted with one or more substituents, preferably withfrom zero to two substituents, independently selected from halo (e.g.,fluoro, chloro, bromo, or iodo), (C₁-C₆)alkyl optionally substitutedwith from one to three fluorine atoms, (C₁-C₆)alkoxy optionallysubstituted with from one to three fluorine atoms, amino, cyano,(C₁-C₆)alkylamino and di-(C₁-C₆)alkylamino; with the proviso that: (a)R⁴ can not be either oxygen or hydroxy when both R² and R³ are hydrogen;(b) when the five membered ring of formula I contains a double bond, R¹¹is absent; (c) when R⁴ is sulfur or oxygen, R⁴ is double bonded to thecarbon to which is attached and such carbon is single bonded to bothadjacent ring nitrogen atoms; and (d) when X is nitrogen and is doublebonded to an adjacent carbon, R¹ is absent. or a pharmaceuticallyacceptable salt thereof. (d) an amount of a compound of the formula

 or a pharmaceutically acceptable salt or solvate thereof wherein: thedashed line in the above formula represents an optional double bondwhere X² is not O; X¹ and X² are each independently selected from O and—(CH₂)_(j)— wherein j is 1 or 2; X³ is —CH(R⁵)N(R⁸)CH(R⁶)—,—CH(R⁵)C(R⁸)(R⁹)CH(R⁶)—, —C(R⁵)═C(R⁸)CH(R⁶)—, or —CH(R⁵)C(R⁸)═C(R⁶)—; R¹and R² are each independently H, hydroxy, or C₁-C₆ alkyl; or R¹ and R²are taken together as a bond; each R³ is independently selected from—S(O)_(j)R⁷ wherein j is an integer ranging from 0 to 2, —C(O)R⁷, —OR⁷,—NC(O)R⁷, —NR⁷R¹², and the substituents provided in the definition of R⁷other than H; R⁴ is absent where the dashed line in the above formula 1represents a double bond or R⁴ is selected from H and the substituentsprovided in the definition of R³; or R³ and R⁴ are taken together withthe carbon atom to which each is attached to form a 5-10 memberedmono-cyclic or bicyclic group wherein said cyclic group may becarbocyclic or heterocyclic with 1 to 3 heteroatoms selected from O, S,and —N(R¹¹)— with the proviso that two O atoms, two S atoms, or an O andS atom are not attached directly to each other; said cyclic group issaturated or partially unsaturated; aromatic or non-aromatic; 1 or 2 ofthe carbon atoms in said cyclic group optionally may be replaced by anoxo —C(O)— moiety; and said cyclic group is optionally substituted by 1to 3 R¹⁰ groups; R⁵ and R⁶ are each independently selected from H andC₁-C₄ alkyl; or R⁵ and R⁶ are taken together as —(CH₂)_(q)— wherein q is2 or 3; or R⁵ or R⁶ is taken together with R⁸ as defined below; each R⁷is independently selected from H, —(CH₂)_(t)(C₆-C₁₀ aryl) and—(CH₂)_(t)(4-10 membered heterocyclic), wherein t is an integer rangingfrom 0 to 5; 1 or 2 of the carbon atoms of said heterocyclic groupoptionally may be replaced with an oxo —C(O)— group; said aryl andheterocyclic R⁷ groups are optionally fused to a benzene ring, a C₅-C₈saturated cyclic group, or a 4-10 membered heterocyclic group; the—(CH₂)_(t)— moieties of the foregoing R⁷ groups optionally include acarbon-carbon double or triple bond where t is an integer between 2 and5; and the foregoing R⁷ groups, except H, are optionally substituted by1 to 5 R¹⁰ groups; R⁸ is selected from the substituents provided in thedefinition of R⁷ other than H; R⁹ is selected from the substituentsprovided in the definition of R⁷; or R⁸ and R⁹ are taken together withthe carbon to which each is attached to form a 5-10 membered mono-cyclicor bicyclic group wherein said cyclic group is carbocyclic orheterocyclic with 1 to 3 heteroatoms selected from O, S, and —N(R¹¹)—with the proviso that two O atoms, two S atoms, or an O and S atom arenot attached directly to each other; saturated or partially unsaturated;aromatic or non-aromatic; 1 or 2 of the carbon atoms in said cyclicgroup optionally may be replaced by an oxo —C(O)— moiety; and saidcyclic group is optionally substituted by 1 to 3 R¹⁰ groups; or R⁸ takentogether with either R⁵ or R⁶ and the separate carbon atoms to whicheach is attached to form a fused 5-10 membered mono-cyclic or bicyclicgroup wherein said cyclic group may be carbocyclic or heterocyclic with1 to 3 heteroatoms selected from O, S, and —N(R¹¹)— with the provisothat two O atoms, two S atoms, or an O and S atom are not attacheddirectly to each other; saturated or partially unsaturated; aromatic ornon-aromatic; 1 or 2 of the carbon atoms in said cyclic group optionallymay be replaced by an oxo —C(O)— moiety; and said cyclic group isoptionally substituted by 1 to 3 R¹⁰ groups; each R¹⁰ is independentlyselected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, halo, cyano,nitro, trifluoromethyl, trifluoromethoxy, azido, —OR¹¹, —C(O)R¹¹,—C(O)OR¹¹, —NR¹²C(O)OR¹¹, —OC(O)R¹¹, —NR¹²SO₂R¹¹, —SO₂NR¹¹R¹²,—NR¹²C(O)R¹¹, —C(O)NR¹¹R¹², —NR¹¹R¹², —S(O)_(j)(C₁-C₆ alkyl) wherein jis an integer ranging from 0 to 2, —(CH₂)_(m)(C₆-C₁₀ aryl),—SO₂(CH₂)_(m)(C₆-C₁₀ aryl), 13 S(CH₂)_(m)(C₆-C₁₀ aryl),—O(CH₂)_(m)(C₆-C₁₀ aryl) and —(CH₂)_(m)(4-10 membered heterocyclic),wherein m is an integer ranging from 0 to 4; said C₁-C₁₀ alkyl groupoptionally contains 1 or 2 hetero moieties selected from O, S and—N(R¹²)— with the proviso that two O atoms, two S atoms, or an O and Satom are not attached directly to each other; said aryl and heterocyclicR¹⁰ groups are optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈saturated cyclic group, or a 4-10 membered heterocyclic group; and saidalkyl, aryl and heterocyclic R¹⁰ groups are optionally substituted by 1to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —NR¹²SO₂R¹¹, —SO₂NR¹¹R¹²,—C(O)R¹¹, —C(O)OR¹¹, —OC(O)R¹¹, —NR¹²C(O)R¹¹, —C(O)NR¹¹R¹², —NR¹¹R¹²,C₁-C₆ alkyl, —OR¹¹ and the substituents listed in the definition of R¹¹;each R¹¹ is independently selected from H, C₁-C₁₀ alkyl,—(CH₂)_(m)(C₆-C₁₀ aryl), and —(CH₂)_(m)(4-10 membered heterocyclic),wherein m is an integer ranging from 0 to 4; said alkyl group optionallyincludes 1 or 2 hetero moieties selected from O, S and —N(R¹²)—, withthe proviso that two O atoms, two S atoms, or an O and S atom are notattached directly to each other; said aryl and heterocyclic R¹¹ groupsare optionally fused to a C₆-C₁₀ aryl group, a C₅-C₈ saturated cyclicgroup, or a 4-10 membered heterocyclic group; and the foregoing R¹¹substituents, except H, are optionally substituted by 1 to 3substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —C(O)R¹², —C(O)OR¹²,—CO(O)R¹², —NR¹²C(O)R¹³, —C(O)NR¹²R¹¹, —NR¹²R¹³, hydroxy, C₁-C₆ alkyl,and C₁-C₆ alkoxy; and, each R¹² and R¹³ is independently H or C₁-C₆alkyl; (e) an amount of a compound of the formula

 or the pharmaceutically acceptable salt thereof, wherein the brokenline represents an optional double bond; a is 0 or 1, wherein when a is0, X may form an optional double bond with the carbon adjacent to V; Vis CHR¹⁰ wherein R¹⁰ is hydrogen or (C₁-C₆)alkyl; T is nitrogen or CH; Xis nitrogen or CR¹¹ wherein R¹¹ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy or cyano; Y and Z are each independently nitrogenor CR¹² wherein R¹² is hydrogen, chloro, bromo, trifluoromethyl,trifluoromethoxy, cyano, (C₁-C₆)alkoxy or (C₁-C₆)alkyl; R¹ is hydrogen,fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or(C₁-C₆)alkyl; R², R⁶, R⁷, R⁸ and R⁹ are each independently selected fromhydrogen, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy,cyano, (C₁-C₆)alkoxy and (C₁-C₆)alkyl; R³ and R⁴ are each independentlyhydrogen or (C₁-C₆)alkyl; and R⁵ is hydrogen, (C₁-C₆)alkoxy,trifluoromethyl, cyano, (C₁-C₆)alkyl or R¹³CO— wherein R¹³ is amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkyl, (C₆-C₁₀)aryl; orwhen a is 1, R¹ and R¹⁰ may be taken together with the carbons to whichthey are attached to form a compound of the formula

 wherein the broken lines represent optional bonds; T, X, Y, Z, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are defined as above; b is 0 or 1; and A and Bare each independently CH, CH₂, oxygen, sulfur, NH or nitrogen; with theproviso that when X is nitrogen, the optional double bond between X andV does not exist; with the proviso that when b is 0, the optional doublebond between A and B does not exist; and with the proviso that when b is1, A and B cannot both be oxygen or sulfur; or (f) an amount of acompound of the formula

 wherein a is oxygen, CH₂, C(CH₃)₂, NR¹⁰, sulfur, SO or SO₂; b isoxygen, CH₂, C═O, C═NR¹¹, C═NOH, SO₂, Sulfur, SO, C═NO(C₁-C₅)alkyl orCR⁷R⁸; each of R¹ through R⁸ is selected, independently, from hydrogen,halo (e.g., chloro, fluoro, bromo or iodo), trifluoromethyl, cyano andhydroxy, or R⁷ and R⁸ together can be C(═O)NH₂ or C(═O)N(C₁-C₄)alkyl,with the proviso that neither R⁷ nor R⁸ can be halo when a is oxygen,NR¹¹, sulfur, SO or SO₂; and each of R¹⁰ and R¹¹ is selected,independently, from hydrogen, benzyl and (C₁-C₆)alkyl; and thepharmaceutically acceptable salts of such compounds or apharmaceutically acceptable salt thereof effective to treat or preventnovelty-seeking disorder in the subject.
 2. The method of claim 1,wherein the novelty-seeking disorder is selected from pathologicalgambling, attention deficit disorder with hyperactivity disorder,substance addiction, drug addiction, alcohol addiction and sexaddiction.
 3. The method of claim 1, wherein the compound is selectedfrom:(7R,9aS)-7(4-fluorophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;(7R,9aS)-7-(3,4-difluorophenoxy)-methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;(7R,9aS)-7-(4-fluorophenoxy)methyl-2-(5-chloropyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2a]-pyrazin-7-ylmethyl]-3H-benzoxazol-2-onehydrochloride;3-[(7R,9aS)-2-(5-chloropyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-3H-benzoxazol-2-one;((7S,9aS)-7-(3-cyanophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido [1,2-a]pyrazine.
 4. The method according to claim 1, whereinsaid compound is selected from the group consisting of:1-[3-(4-pyridin-2-yl-piperazin-1-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;1-{3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;1-{3-[4-(5-chloro-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;1-{3-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one;1-[3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-propyl]-1,3-dihydro-benzoimidazol-2-one;and1-{3-[4-(6-chloro-pyridazin-3-yl)-piperazin-1-yl]-propyl}-1,3-dihydro-benzoimidazol-2-one.5. The method according to claim 1, wherein said compound is selectedfrom the group consisting of:1-Benzoimidazol-1-yl-3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol;1-(5-Chloro-benzoimidazol-1-yl)-3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol;1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-5-trifluoromethyl-1H-benzoimidazole;1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-1H-benzoimidazole;1-{3-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-propyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one;1-Benzoimidazol-1-yl-3-(4-o-tolyl-piperazine-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-(4-m-tolyl-piperazine-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-(4-p-tolyl-piperazin-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-{4-chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-(4-naphthalen-1-yl-piperazin-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-(4-benzyl-piperazin-1-yl)-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-[4-(2-ethoxy-benzyl)-piperazin-1-yl]-propan-2-ol;1-Benzoimidazol-1-yl-3-{4-{3-(3-trifluoromethyl-phenyl)-propyl]-piperazin-1-yl}-propan-2-ol;and1-Benzoimidazol-1-yl-3-{4-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-propan-2-ol.6. The method according to claim 1 wherein said compound is selectedfrom the group consisting of:(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2′-one;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2′-phenyl-octahydro-pentalen-2′ol,maleate salt;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one,ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-hexahydropentalene-2-one;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-hydroxy-5′-phenyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile,maleate salt;(2′α,3′aβ,5′α,6′aβ)-5-Hydroxy-5-phenyl-hexahydro-pentalen-2-one;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2′-phenyl-octahydro-pentalen-2′ol, maleate salt;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-1-pyrimidyl)-piperazin-1-yl]-2′-(4-fluoro-phenyl)-octahydro-pentalen-2′ol, maleate salt;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-2′-(4-fluoro-phenyl)-octahydro-pentalen-2′ol, maleate salt;(2′α,3′aβ,5′α,6′aβ)-5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2′-(4-fluoro-phenyl)-octahydro-pentalen-2′ol,maleate salt; (2′α,3′aβ,6′aβ)-1-(4-Fluoro-phenyl)-4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazinedihydrochloride;(2′α,3′aβ,6′aβ)-5-Fluoro-2-[4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine maleate;(2′α,3′aβ,6′aβ)-2-Fluoro-4-[4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile,maleate;(2′α,3′aβ,6′aβ)-2-Fluoro-4-{4-[5-(2-methoxy-phenyl)-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile, maleate;(2′α,3′aβ,6′aβ)-1-Phenyl-4-(5′-phenyl-1′,2′,3′,3′a,4′,6′a-hexahydro-pentalen-2′-yl)-piperazine, dimaleate;(2′α,3′aβ,5′α,6′aβ)-1-(4-Fluoro-phenyl)-4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazine,dihydrochloride;(2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine, maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-(5′-phenyl-octahydro-pentalen-2′-yl)-piperazine,maleate;(2′α,3′aβ,5′α,6′aβ)-5′-Hydroxy-5′-(2-trifluoromethyl-phenyl)-hexahydro-pentalen-2′-one;(2′α,3′aβ,6′aβ)-(2-trifluoromethyl-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen -2′-one, ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-5′-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2′-one, ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-5′-(2-Trifluoromethyl-phenyl)-hexahydro-1H-pentalen-2′-one;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-trifluoromethyl-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-{4-[5′-(2-methoxy-phenyl)-octahydro-pentale-2′-yl]-piperazin-1-yl}-pyrimidine, maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(3-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(4-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine, maleate;(2′α,3′aβ,5′α,6′aβ)-5-Chloro-2-{4-[5′-(2-methoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-pyrimidine,maleate;(2′α,3′aβ,5′α,6′aβ)-5-Chloro-2-[4-(5′-o-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-pyrimidine, maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-methanesulfonyl-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate; (2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-[5′-(3-pyrrolidin-1-ylmethyl-phenyl)-octahydro-pentalen-2′-yl]-piperazine, dimaleate;5-Trimethylstannayl-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethyleneketal; 5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one;(2′α,3′aβ,5′α,6′aβ)-2-Cyano-4-{4-[5′-(2-fluoro-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-trifluoromethoxy-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-fluoro-phenyl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate; (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-pyridin-2-yl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile,dihydrochloride;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-m-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(5′-p-tolyl-octahydro-pentalen-2′-yl)-piperazin-1-yl]-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-N-(2-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin1-yl]-octahydro-pentalen-2′-yl}-phenyl)-acetamide,maleate; (2′α,3′aβ,5′α,6′aβ)-N-(2-{5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1yl]-octahydro-pentalen-2′-yl}-phenyl)-acetamide, maleate;5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethyleneketal; 2-(5-Oxo-octahydro-pentalen-2-yl)-benzamide, ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-2-{5′-[4-(4-Cyano-3-fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-benzamide,maleate; (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate; (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate; (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-piperazin-1-yl]-pyrimidine;(2′β,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydrospiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-piperazin-1-yl]-pyrimidine;(2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydro-3′a,6′a-dimethylspiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-pyrimidine,maleate; (2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-[4-(3′,3′a,4′,5′,6′,6′a-hexahydro-3′a,6′a-dimethylspiro[isobenzofuran-1(3H),2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-pyrimidine,maleate; (2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile,maleate; (2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl)-1-piperazinyl]-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-1-Phenyl-4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-piperazine,maleate; (2′β,3′aβ,5′α,6′aβ)-1-Phenyl-4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-piperazine,maleate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-1-piperazinyl]-benzonitrile,maleate; (2′β,3′aβ,5′α,6′aβ)-2-Fluoro-4-[4-(3,3′,3′a,4,4′,5′,6′,6′a-hexahydrospiro[2H-6-fluoro-1-benzopyran-2,2′(1′H)-pentalen]-5′-yl]-5′-yl)-1-piperazinyl]-benzonitrile,maleate; (2′α,3aβ,5′α,6aβ)-5-Benzylamino-hexahydropentalen-2-one,mono-ethylene ketal; (2α,3aβ,5α,6aβ)-5-Amino-hexahydropentalen-2-one,mono-ethylene ketal;(2α,3aβ,5α,6aβ)-5-(5-Fluoro-2-ntro-phenylamino)-hexahydropentalen-2-one,mono-ethylene ketal;(2α,3aβ,5α,6aβ)-5-(2-Amino-5-fluoro-phenylamino)-hexahydropentalen-2-one,mono-ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(6-fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,dimesylate;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile, mesylate;(2′α,3′aβ,5′α,6′aβ)-1-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one,mesylate;(2α,3aβ,5α,6aβ)-5-(6-Fluoro-2-methyl-benzoimidazol-1-yl)-hexahydro-pentalen-2-one;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(6-fluoro-2-methylbenzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,dimesylate;(2′α,3′aβ,5′α,6′aβ)-6-Fluoro-2-methyl-1-[5′-(4-phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]-1H-benzoimidazole,dimaleate; (2α,3aβ,6aβ)-5-(1H-Indol-3-yl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, mono-ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-2-Fluoro-4-{4-[5′-(1H-indol-3-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-3-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]-1H-indole, maleate;(2α,3aβ,6aβ)-5-(4-Fluoro-phenoxy)-hexahydro-pentalen-2-one;(2′α,3′aβ,5′β,6′aβ)-1-[5′-(4-Fluoro-phenoxy)-octahydro-pentalen-2′-yl]-4-phenyl-piperazine,maleate;(2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-{4-[5′-(4-fluoro-phenoxy)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile, maleate;(2′α,3′aβ,5′α,6′aβ)-5-Fluoro-2-{4-[5′-(4-fluoro-phenoxy)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-pyrimidine, maleate;(2′β,3′aβ,5′β,6′aβ)-1-[5′-(4-Fluoro-phenoxy)-octahydro-pentalen-2′-yl]-4-phenyl-piperazine, maleate;(2′α,3′aβ,5′β,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]-isoindole-1,3-dione maleate;(2′α,3′aβ,5′α,6′aβ)-5-Hydroxy-hexahydro-pentalen-2-one, ethylene ketal;(2′α,3′aβ,5′α,6′aβ)-2-Oxo-3-(5-oxo-octahydro-pentalen-2-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester, ethyleneketal;(2′α,3′aβ,5′α,6′aβ)-2-(5-oxo-octahydro-pentalen-2-yloxy)-3H-benzoimidazole-1-carboxylic acid tert-butyl ester, ethylene ketal;(2′β,3′aβ,5′α,6′aβ)-3-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butylester; (2′β,3′aβ,5′α,6′aβ)-1-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one,maleate;(2′α,3′aβ,5′β,6′aβ)-2-Fluoro-4-{4-[5′-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-benzonitrile,maleate;(2′β,3′aβ,5′α,6′aβ)-1-{5′-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-1,3-dihydro-benzoimidazol-2-one,maleate; (2′β,3′aβ,5′α,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yloxy]-1H-benzoimidazole, maleate;(2′α,3′aβ,5′α,6′aβ)-2-(5-Oxo-octahydro-pentalen-2-yl)-isoindole-1,3-dione;(2′α,3′aβ,5′β,6′aβ)-2-[5′-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2′-yl]isoindole-1,3-dione,maleate;(2′α,3′aβ,5′β,6′aβ)-4-{4-[5′-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-octahydro-pentalen-2′-yl]-piperazin-1-yl}-2-fluoro-benzonitrile, maleate;(2′α,3′aβ,5′β,6′aβ)-2-{5′-[4-(5-Fluoro-pyrimidin-2-yl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione, maleate;(2′β,3′aβ,5′α,6′aβ)-2-{5′-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione, maleate;(2′β,3′aβ,5′α,6′aβ)-2-{5′-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-octahydro-pentalen-2′-yl}-isoindole-1,3-dione, maleate; and,(2′β,3′aβ,5′α,6′aβ)-N-[5-(4-Phenyl-piperazin-1-yl)-octahydro-pentalen-2-yl]-benzamide, maleate.
 7. The method of claim 1, the compound isselected from the group consisting of:2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;5-Fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole;5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-indole;5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;2-[4-(6-Chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole;5-Fluoro-2-(4-[5′-fluoro]pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole;5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-azaindole; and2-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-1H-azaindole.
 8. A methodof treating or preventing a novelty-seeking disorder in a subject,comprising administering to the subject an amount of a dopamine D4receptor ligand, or a pharmaceutically acceptable salt thereof,effective to treat or prevent a novelty-seeking disorder in the subject.9. The method of claim 8, wherein the novelty-seeking disorder isselected from pathological gambling, attention deficit disorder withhyperactivity disorder, substance addiction, drug addiction, alcoholaddiction and sex addiction.